The overall scientific goal for the proposed research is to develop and apply novel synthetic methods and strategies toward the construction of fused carbocyclic structures analogous to those found in the biologically active phorbol family (tigliane skeleton) of natural products and structurally related ingenol derivatives. Some of these compounds are strong activators of the enzyme protein kinase C which has been shown to play a major role in cellular signal transduction, while other members of this class elicit different biological responses, including anti-HIV as well as anti-tumor activity. The proposed synthetic strategy for the assembly of the tigliane ring system relies on a unique and highly efficient tandem sequence that involves the intramolecular cyclization of appropriately substituted 4-pentyn-l-ols followed by a [3,3]-sigmatropic rearrangement of the resulting 2-alkylidene-tetrahydro-furan intermediates. This basic ring construction strategy will be coupled with other synthetic methodologies to generate structurally and functionally diverse analogues of phorbol and ingenol.